1. Field of the Invention
The present invention relates to a medicinal drug, and in particular, to a novel lactam compound having sugar transport enhancement action and having excellent hypoglycemic action, a preparation method thereof, and a preparation intermediate thereof.
The present invention also relates to a pharmaceutical composition comprising the lactam compound.
2. Discussion of the Background
Medicinal treatment of type II diabetes is positioned as a therapeutic method for patients for whom sufficient improvement cannot be seen by nutritional therapy or exercise therapy, and so far, formulations using insulin, which is an endogenous hormone in charge of hypoglycemic action, or peroral hypoglycemic agent having actions such as promotion of insulin secretion or improvement of peripheral insulin resistance have been developed. Currently, methods using a peroral hypoglycemic agent to adjust blood glucose stringently are the mainstream medicinal treatments of type II diabetes; however, in cases where sufficient insulin action to correct for hyperglycemia cannot be obtained, insulin therapy is carried out as major means. Meanwhile, administration of insulin therapy is the sole treatment with respect to type I diabetes, as insulin secretion capability of the patient is abolished.
Although used as an important therapy as stated above, insulin therapy, being an injectable agent, has the problems such as cumbersome procedure and education of the patients, and from the aspect of improving compliance, improvement of the administration method is strongly desired. In recent years, some attempts have been made in the development of insulin administration method by various non-injection formulations substituted for injectables; however, due to problems such as the absorption efficiency is low and the absorption does not stabilize, they are not in practical use.
As one major hypoglycemic action of insulin, the action of enhancing the sugar transport capability of peripheral cells to cause the blood sugar to be taken up by the peripheral cells, consequently decreasing the blood glucose level, may be cited. It is expected that if a novel oral medicine that would drop the blood glucose level by enhancing the sugar transport action of peripheral cells could be found, it would become a promising therapy against diabetes mellitus diseases.
As a lactam compound having the action of enhancing sugar transport of peripheral cells and having the action of decreasing the blood glucose level, compound represented by the following formula and the synthesis methods thereof are known (Patent Reference 1: International Publication WO02/44180 A1 brochure, Patent Reference 2: U.S. Patent Application Disclosure Publication US2004/0048847 A1, Patent Reference 3: International Publication WO2004/069259 A1 brochure). However, there is no concrete description of the compound of the present invention.
wherein A represents an aromatic ring, a heterocycle and an aliphatic ring.
In addition to the above, as compounds having the action of enhancing sugar transport of peripheral cells and having the action of decreasing blood glucose level, the compounds described in International Publication WO00/71506 A1 brochure (Patent Reference 4), International Publication WO02/40485 A1 brochure (Patent Reference 5) as well as in J. Biol. Chem. 2002, 277, 46 (15), 43565 (Non-Patent Reference 1) are known; however, they have structures that are totally different from the compound of the present invention. In addition, these are not in practical use as medicinal products.
In addition, regarding compounds having a lactam structure, several compounds have been reported (Non-Patent Reference 2: Khim. Farm. Zh. 1991, 25 (11); Non-Patent Reference 3: Pharmaceutical Chemical Journal, 1991, 25 (11), 768; Non-Patent Reference 4: pharmaceutical sciences journal, 1986, 715; Non-Patent Reference 5: Chem, Pharm. Bull. 1984, 3724; Non-Patent Reference 6: Journal of the Pharmaceutical Society of Japan, 1984, 1004; Non-Patent Reference 7: J. Org. Chem. 1983, 4367). However, they have structures that are different from the compound of the present invention, furthermore, the relationship between these compounds and the action of enhancing sugar transport of peripheral cells or the action of decreasing blood glucose level is not reported at all.